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. 2019 Jun 13;10(6):468.
doi: 10.1038/s41419-019-1706-y.

Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans

Lingyan Wu  1   2 , Mingfeng Xia  3   4 , Yanan Duan  1 , Lina Zhang  1 , Haowen Jiang  1 , Xiaobei Hu  1 , Hongmei Yan  3   4 , Yiqiu Zhang  5 , Yushen Gu  5 , Hongcheng Shi  5 , Jia Li  6 , Xin Gao  7   8 , Jingya Li  9
Affiliations

Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans

Lingyan Wu et al. Cell Death Dis. .

Abstract

Brown adipose tissue (BAT) dissipates metabolic energy and mediates non-shivering thermogenesis, thereby boosting energy expenditure. Increasing BAT mass and activity is expected to be a promising strategy for combating obesity; however, few medications effectively and safely recruit and activate BAT in humans. Berberine (BBR), a natural compound, is commonly used as a nonprescription drug to treat diarrhea. Here, we reported that 1-month BBR intervention increased BAT mass and activity, reduced body weight, and improved insulin sensitivity in mildly overweight patients with non-alcoholic fatty liver disease. Chronic BBR treatment promoted BAT development by stimulating the expression of brown adipogenic genes, enhanced BAT thermogenesis, and global energy expenditure in diet-induced obese mice and chow-fed lean mice, Consistently, BBR facilitated brown adipocyte differentiation in both mouse and human primary brown preadipocytes. We further found that BBR increased the transcription of PRDM16, a master regulator of brown/beige adipogenesis, by inducing the active DNA demethylation of PRDM16 promoter, which might be driven by the activation of AMPK and production of its downstream tricarboxylic acid cycle intermediate α-Ketoglutarate. Moreover, chronic BBR administration had no impact on the BAT thermogenesis in adipose-specific AMPKa1 and AMPKa2 knockout mice. In summary, we found that BBR intervention promoted recruitment and activation of BAT and AMPK-PRDM16 axis was indispensable for the pro-BAT and pro-energy expenditure properties of BBR. Our findings suggest that BBR may be a promising drug for obesity and related metabolic disorders in humans partially through activating BAT.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1. BBR increases the mass and activity of BAT in NAFLD patients.
a 18F-FDG PET/CT images in representative subject of the 10 before and after BBR intervention. b Mean cold-activated standard uptake value (SUV) in BAT regions. c The maximal SUV in BAT regions. d Detectable BAT volume. e BAT activity as reflected by 18F-FDG uptake. f The linear regression of BAT activity change percentage and body weight change percentage after BBR intervention. g The linear regression of BAT activity change percentage and HOMA-IR change percentage after BBR intervention. n = 10. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by paired Student’s t test
Fig. 2
Fig. 2. Chronic BBR treatment enhances BAT thermogenesis and reduces obesity in diet-induced obese (DIO) mice.
a–c Body weight, food intake, and tissue weight of DIO mice after treatment. n = 7–8. d Rectal temperature of DIO mice. n = 7–8. e–h O2 consumption e–f and energy expenditure g–h of DIO mice under basal and CL 316,243-stimulated conditions. n = 7–8. i–o 18F-FDG PET/CT imaging of DIO mice: representative 18F-FDG PET/CT images with dashed lines marking the interscapular BAT region i; Maximal SUV j, mean SUV k, estimated BAT volume l, and total 18F-FDG uptake (kBq) m in BAT. The maximal and mean SUV in iWAT n and eWAT o. n = 4. p–r Representative H&E staining and UCP1 IHC images of BAT in DIO mice after treatment p; Quantification of nuclei number of brown adipocytes per field q. Relative UCP1 protein expression in BAT depicted by relative integrated optical density (IOD %) r. n = 7–8, 4–8 slides/mouse. s Relative mRNA levels of indicated genes in BAT after treatment for 17 days. n = 6. t–u Western blot analysis t and relative integrated density u of indicated protein in BAT of DIO mice after treatment. n = 7–8. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with vehicle by Student’s t test
Fig. 3
Fig. 3. BBR promotes brown differentiation in both mouse and human brown preadipocytes.
a–h BAT-SVF cells on day 8 of differentiation: representative oil red O staining and immunofluorescence staining of UCP1 (green) and Hoechst (blue) a, Rosiglitazone (Rosi) as a positive control; relative optical density (OD) measurement at 520 nm b; UCP1-positive cell ratio c; relative mRNA level of indicated genes (BBR 0.25 μM) d; western blot analysis of indicated proteins e–f, β-actin was used as loading control; Basal, uncoupled, and maximal OCR g–h. i–n Human fetal brown preadipocyte at day 14 of differentiation: representative oil red O staining images i and relative OD measurement at 520 nm j; representative western blot analysis of indicated protein levels k; relative integrated density of UCP1/β-actin were determined l. Basal, uncoupled, and maximal OCR m–n. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with vehicle by Student’s t test or one-way ANOVA followed by Dunnett’s multiple comparisons for comparison of two or more groups
Fig. 4
Fig. 4. PRDM16 played an indispensable role in BBR-induced brown adipogenesis.
a–d ChIP-qPCR analysis for PRDM16, MED1, PolII, and PGC-1α binding to indicated genes in differentiated C3H10-T1/2 cells on day 8 of differentiation. e–g The mRNA levels of the indicated genes e, representative western blot images of the indicated proteins f and average OCR g in scramble or shPRDM16 stable cells on day 8 of differentiation. h Rectal temperature of BAT-specific PRDM16 knockdown mice and WT mice (NC) at 4 °C for 7 h after 3 weeks treatment. n = 8–9. i The expression levels of brown fat-enriched genes in BAT of BAT-specific PRDM16 knockdown mice and NC mice after 6 weeks treatment. n = 8–9. j Western blot analysis and relative integrated density of indicated proteins in BAT of BAT-specific PRDM16 knockdown mice and NC mice after 6 weeks treatment. n = 4. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with Veh or Scramble-Veh or NC-Veh by Student’s t test
Fig. 5
Fig. 5. BBR epigenetically decreased the DNA methylation level of PRDM16 promoter.
a–c The levels of α-KG, succinate, fumarate, and malate in BAT a, iWAT b, and eWAT c of DIO mice after 6 weeks treatment. n = 10. d–g The α-KG d, succinate e, fumarate f, and malate g level in C3H10-T1/2 cells during brown differentiation. h The activity of TETs in C3H10-T1/2 cells at day 4 of differentiation. i–j The enrichment levels of 5-mC i and 5-hmC j in Prdm16 promoter of C3H10-T1/2 cells at day 4 of differentiation. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with vehicle by Student’s t test or one-way ANOVA followed by Dunnett’s multiple comparisons for comparison of two or more groups
Fig. 6
Fig. 6. BBR-promoted brown adipogenesis and thermogenesis were depended on AMPK signaling.
13 weeks-old male AKO mice and floxed mice were treated with saline or BBR for 8 weeks. a–b Body weight a and food intake b were monitored during the treatment. n = 9–10. c The relative fat, fluid, and lean mass of the AKO and floxed mice after 8 weeks treatment. n = 9–10. d Relative weight of liver and different adipose depots of AKO mice and floxed mice after 8 weeks treatment. n = 9–10. e–h The VO2 change e, average VO2 f, EE change g, and average EE h of AKO and floxed mice after 4 weeks treatment under basal condition and after single injection with CL 316,243. n = 8. i–k The rectal temperature i, interscapular skin temperature j and representative thermal images of AKO and floxed mice housed at 4 °C for 7 h k after 6 weeks treatment. n = 9–10. l–m Representative western blot images d and the relative integrated density e of indicated proteins in BAT of AKO and floxed mice after 6 weeks treatment. n = 5–6. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared with Flox-Veh group by Student’s t test
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